Process for the preparation of steroidal dienes and intermediates obtained thereby



2,897,213 Patented July 28, 1959 2,897,216 PROCESS FOR THE PREPARATION OF STEROIDAL DENES AND INTERMEDIA'IES OBTAINED THEREBY Eugene P. Uliveto, Bloomfield, and David H. Gould, Leonia, N..l., assignors to Schering Corporation, Bloomfield, N.J., a corporation of New Jersey No Drawing. Application November 1, 1954 Serial No. 466,207 10 Claims. (Cl. 260-39145) invention have the following structural formulae:

(IJHEOR ll'l-IzO-R C 00 I OH In the above formulae, R is H or acyl, the acyl group being preferably lower alkanoyl, such as formyl, acetyl, propionyl, butyryl and valeryl, and especially acetyl.

It is the general object of the present invention to provide a chemical procesfor producing Compounds I and II from available or readily obtainable saturated pregnan-17u,21-diol-3,20-diones havingin the ll-position aketo or an aor S-hyd-roxy group, and likewise from :the- 21-esters of such compounds, the nucleus being of either normal or allo configuration. 7

(1) (EHEOR Q dimethyl aniline.

It is a further object of the invention to provide 2,4- dihalogenides of the above-mentioned starting materials from which the above-mentioned steroidal dienes may be readily obtained.

We have found that the 2l-esters of pregnan-Hulldiol-3,11,20-trione and of pregnan-11,l'/Ta,2l-triol-3.,20- dione, can be halogenated at the 2- and 4-positions by treatment with one or more halogens having anatomic Weight higher than that of fluorine, to produce the corresponding 2,4-dihalogenides in satisfactory yield. The halogenation at the two positions can be carried out in one or two steps, and in the latter case, different halogens may be employed like chlorine and bromine. The dihalogenide is then treated with a dehydrohalogenating agent to introduce two double bonds into ring A at the 1,2- and 4,5-positions, yielding Compound lb or 11b. The resulting diene ester can then, if desired, be hydrolyzed in known manner with an acid or base to produce the primary alcohol of the dienes (Ia and Ha).

We prefer to employ bromine as the halogenating agent and the invention will accordingly be further described in connection with the use of such halogen. With bromine, the 2,4-dibromides of the 2l-esters of pregnan- 17a,2'1-diol'-3,11,20-trione and of pregnan-11,17eg21-triol- 3,20-dione can be readily obtained in good yield. We prefer to effect the dehydrobromination by refluxing with collidine, followed by chromatographic separation of the 1,4-d'iene-21-ester. In place of collidine, other high-boilingv organic bases can be employed, like quinaldine and Our process is applicable to the allo as well as to the normal pregnan series. Thus, dibromination of allopregnan-17u,21-diol-3,11,20-trione ZI-acetate and of allopregnan-l1p,17a,21-triol-3,20-dione 21-acetate yields the corresponding dibromides (III and Illa) which upon dehydrobromination give the Zl-acetates of the dienes I and II, respectively.

The dienes of lla-hydroxylated steroids can also be prepared in the same manner. Dibromination of pregnan-11a,17u,2I-triol-3,20-dione 21-acetate gives the corresponding 2,4-dibromide (IV) which, upon dehydrohalogenation, gives A -pregnadien-l1a,17a,21-triol3,20 dione 2l-acetate (V). Oxidation of V gives Ib (R=acetyl) in good yield. Hydrolysis of V gives A -pregnadien- 11m,17a,21-triol-3,20-dione (VI) which, upon oxidation, gives Ia.

The reactions involved in the present invention are typified by the following equations:

OHzOR The novel intermediates obtained by the present invention may be represented by the following formula:

CHzOR X I Br I and R is a member of the group consisting of H and lower alkanoyl.

The bromination of the starting compound, which is preferably a 21-ester, is conducted in acetic acid or other substantially anhydrous organic solvent which is inert toward the bromine. It is not necessary to purify the so-formed dibromide prior to reaction with the dehydrobrominating agent which, as already stated, is preferably a high-boiling organic base, collidine being generally most suitable. The resulting doubly unsaturated ester can then, if desired, be hydrolyzed with an alkali metal base,

such as carbonates, bicarbonates, and hydroxides in known manner in a suitable neutral solvent like methyl and ethyl alcohols.

In the case of the ll-hydroxy compounds, and particularly the Ila-hYdlOXY compounds, such hydroxyl group can be oxidized to a keto group either before or after the hydrolysis. While various oxidizing agents may be employed, we have found chromic acid to be an eflicient and inexpensive agent for this purpose.

As above indicated, the present invention contemplates the use, among other compounds, of allopregnan-17,2ldiol-3,11,20-trione 2l-ester (preferably the acetate) and the corresponding ll-dihydro compound (llp-hydroxyl), and we describe by way of illustration in Examples A and B hereinbelow suitable methods for the preparation of these starting compounds:

EXAMPLE A Allopregnan-I 7a,21-di0l-3,11,20-trione 21 -acetate A solution of 2.00 g. of cortisone acetate (A -pregnen- 17a,21-diol-3,11,20-trione 2l-acetate) in 200 ml. of ethyl acetate is hydrogenated with hydrogen at atmospheric pressure and room temperature using 0.20 g. of 5% palladium on charcoal as catalyst. The reaction is allowed to proceed overnight, the catalyst then removed by filtration and the filtrate evaporated under reduced pressure. The residue is crystallized from acetone to yield allopregnanl7a,21-diol-3,ll,20-trione 2l-acetate.

EXAMPLE B A-llopregnan-I 1,8,1 70;,21 -diol-3,11 ,20-trione 21 -acetate In a similar fashion 50 g. of Compound F ZI-acetate methanol for mminutes at reflux gives -A -pregnadiena, 1veZ -1riQ -3 9d 1 l r V Oxidation of the acetate (11b) With CrQ ,N-bromoacetamide, or N-bromosuccinimide yields Ib, While oxida- (l rrcgn ni t Zr -l l0 -l n 21 acu in mm of with Nbromoacetamide or N- bl'omosuccini 750 ml. of ethyl acetate are hydrogenated with hydrogen in the presence of.0.5 g. of 5% palladium on charcoal catalyst to, give allopregnan-lilfi,17a,2"1-triol-3,20-dione 21-acetate.

Suitable methods for the preparation of the dienes of the present invention are described in the following examples, it being understood that these are presented solely by way of illustration and not as indicating the limits of the invention.

EXAMPLE 1 A solution of 1 g. of allopregnan-l70,21-di0l-3,11,20- trione 2l-acetate in ml. of acetic acid is brominated by the addition of 0.80 g. of bromine in 10 ml. of acetic acid. Addition of water precipitates the 2,4-dibromoallopregnan-17a,21-diol-3,11,20-trione Zl-acetate.

Without purification, the dibromide (1.5 g.) is refluxed in 50 m1. of S-collidine for 1 hour. Chloroform and Water are added, the organic extract Washed with dilute sulfuric acid, then with water, and dried and evaporated. The crude product is chromatographed on Florisil to give 1,4-pregnadien-17a,2l-diol-3,11,20-trione-21-acetate (Ib, R acetyl) M.P. 232-235 (dec.).

EXAMPLE 2 In the manner described in Example 1, pregnan-lh, 21-diol-3,11,20-trione 21-acetate is brominated with 2 equivalents of bromine, and dehydrobrominated by means of collidine to yield Ib.

EXAMPLE 3 In a similar fashion, allopregnan-llB,l7e,2l-triol-3,20- dione 21-acetate is brominated at positions 2 and 4, and dehydrobrominated with collidine to give A -pregnadien- 11/3,17a,21-triol-3,20-dione 21-acetate (Ilb, R=acetyl) M.P. 234-238"; [or] +114 (dioxane), 6243 max. 15,000 (MeOH).

EXAMPLE 4:

In a similar fashion, pregnan-l1,8,17u,21-tri0l-3,20- dione 21-acetate is dibrominated with 2 moles of bromine and dehydrobrominated with collidine to give IIb.

EXAMPLE 5 A mixture of 1.0 g. of the 21-acetate of 1,4-pregnadien- 17a,21-dio1-3,11,20-trione, ml. of methanol, 5 ml. of water and 0.3 g. of potassium bicarbonate is refluxed 10 minutes, the excess alkali neutralized with acetic acid, and the methanol removed under reduced pressure to precipitate 1,4-pregnadiene-17a,21 diol 3,11,20 trione (Ia), M.P. 230-233 [OC]D+174 (dioxane), 5238 max. 15,500 (MeOH).

EXAMPLE 6 In the manner described in Example 5, the 2l-acetate of 1,4-pregnadien-11p,17u,2l-triol-3,20-dione is hydrolyzed with potassium bicarbonate in aqueous methanol to give the free alcohol (11a), M.P. 238241, [OL]D:105 (dioxane), 6243 max. 14,700 (MeOH).

EXAMPLE 7 I I mide gives Ia.

The present application is a continuation-in-part of our mp udi s appl cat on Serial ,No. 308,502, filed :Septernrbe .19 2, .HOW U.S- Paten ..2,'71 H 1. In a process for the manufacture of 1,4-pregnadien- 17a,21-diol-3,11,20-trione and its 2l-acetate, the steps which comprise reacting pregnan-11a,17 oc,21-t1i0l3,2()- dione ZI-acetate with bromine to form the 2,4-dibromide, heating and reacting the dibromide with a high boiling organic base to effect di-dehydrobromination and produce the corresponding 1,4-pregnadiene compound, and oxidizing the 1 IOL-hYdI'OXY]. to a keto group.

2. Process according to claim 1, including the step of hydrolyzing the 21-acetate group.

3. In a process for the manufacture of 1,4-pregnadien- 11 8,17a,21-triol-3,20-dione and its 21-acetate, the steps Which comprise reacting allopregnan-l1B,17a,21-triol-3, 20-dione 21-acetate with bromine to form the 2,4-dibromide, and heating and reacting the dibromide With a high boiling organic base to etfect di-dehydrobromination and form the corresponding 1,4-pregnadiene compound.

4. In a process for the manufacture of 1,4-pregnadien- 11p ,17a,21-trio1-3,20-dione and its 21-acetate, the steps which comprise reacting pregnan-llfi,17a,2l-triol-3,20- dione 21-acetate with bromine to form the 2,4-dibromide, and heating and reacting the dibromide with a high boiling organic base to eifect di-dehydrobromination and form the corresponding 1,4-prcgnadiene compound.

5. Process according to claim 3, including the step of hydrolyzing the ZI-acetate group.

6. The process which comprises di-dehydrobrominating an allopregnane of the formula CHzOR no J Br i wherein R is lower alkanoyl, the step which comprises heating and reacting a compound of the group consisting of normal and allo-pregnane-2,4-dibromo11,9,17ot-di01- 7 r 8 21-OR-3,20-'diones, wherein R is' as abovedefined, with 2,773,075 Wilsoif et a1. 2.2;; Dec. 4, 1956 a high-boiling organic base, until di-dehydrobromination 2,852,539 Day et a1. Sept. 16, 1958 has been effected at the 1,2- and 4,5-positions. V

" OTHER REFERENCES References Cited in the file of this patent 5 Rosenk rafiz: Jour. Am. Chem. Soc., 72, 4081-85 UNITED STATES PATENTS V 1950 V V V e .7 2,579,479 Djeras si Dec. 25, 1951 2g i?i ;l f 2,659,744 schnelder 1953 Butenandt: Ben, 72, 1617-23 1939 2,703,805 Rosenkranz Mar. 8, 1955 10 

7. 2,4-DIBROMOPREGNANE-11B,17A,21-TRIOL-3,20-DIONE 21 ACETATE.
 10. IN A PROCESS FOR THE MANUFACTURE OF COMPOUNDS OF THE FORMULA: 